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Antisense Bcl-2 oligodeoxynucleotides inhibit progression to androgen-independence after castration in the Shionogi
H Miyake1, A Tolcher, M E Gleave
1The Prostate Centre, Vancouver General Hospital, British Columbia, Canada.
Abstract:
Progression to androgen-independence remains the main obstacle to improving survival for patients with advanced prostate cancer. Although Bcl-2 expression in normal prostatic epithelial cells is low or absent, Bcl-2 is highly up-regulated in prostate cancer cells after androgen withdrawal and during progression to androgen-independence. Here, we test the efficacy of antisense Bcl-2 oligodeoxynucleotide (ODN) therapy administered adjuvantly after castration to delay time to androgen-independent recurrence in the androgen-dependent mouse Shionogi tumor model. Treatment of Shionogi tumor cells in vitro with antisense Bcl-2 ODN inhibited Bcl-2 expression in a dose-dependent and sequence-specific manner. Systemic administration of antisense Bcl-2 ODN in mice bearing Shionogi tumors beginning 1 day postcastration resulted in a more rapid regression of tumors and a significant delay of emergence of androgen-independent recurrent tumors. Furthermore, despite significant reduction of Bcl-2 expression in tumor tissues, antisense Bcl-2 ODN had no effect on Bcl-2 expression in normal mouse organs. These findings illustrate the potential utility of antisense Bcl-2 therapy for prostate cancer in an adjuvant setting with androgen ablation.
Insights
Antisense Bcl-2 oligodeoxynucleotide (ODN) therapy effectively reduced Bcl-2 expression in prostate cancer cells. This approach delayed androgen-independent recurrence in a mouse model, showing potential for adjuvant prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Androgen-independence is a major challenge in advanced prostate cancer treatment.
- Bcl-2 is upregulated in prostate cancer cells during progression to androgen-independence.
- Targeting Bcl-2 offers a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy of antisense Bcl-2 oligodeoxynucleotide (ODN) therapy.
- To determine if adjuvant antisense Bcl-2 ODN therapy can delay androgen-independent recurrence after castration.
- To assess the specificity of antisense Bcl-2 ODN in prostate cancer models.
Main Methods:
- In vitro treatment of Shionogi tumor cells with antisense Bcl-2 ODN.
- Systemic administration of antisense Bcl-2 ODN in mice with androgen-dependent Shionogi tumors postcastration.
- Monitoring tumor regression and emergence of androgen-independent recurrent tumors.
- Assessing Bcl-2 expression in tumor tissues and normal mouse organs.
Main Results:
- Antisense Bcl-2 ODN inhibited Bcl-2 expression in a dose-dependent and sequence-specific manner in vitro.
- Systemic antisense Bcl-2 ODN treatment led to more rapid tumor regression.
- A significant delay in the emergence of androgen-independent recurrent tumors was observed.
- Antisense Bcl-2 ODN reduced Bcl-2 expression in tumors but not in normal organs.
Conclusions:
- Antisense Bcl-2 ODN therapy is effective in reducing Bcl-2 expression in prostate cancer cells.
- Adjuvant antisense Bcl-2 ODN therapy can delay androgen-independent recurrence in prostate cancer.
- This therapy shows potential for use alongside androgen ablation in prostate cancer treatment.
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